The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells

• Published in: Blood Vol. 123; no. 19; pp. 2988 - 2996
• Main Authors: Zhang, Jenny, Jima, Dereje, Moffitt, Andrea B., Liu, Qingquan, Czader, Magdalena, Hsi, Eric D., Fedoriw, Yuri, Dunphy, Cherie H., Richards, Kristy L., Gill, Javed I., Sun, Zhen, Love, Cassandra, Scotland, Paula, Lock, Eric, Levy, Shawn, Hsu, David S., Dunson, David, Dave, Sandeep S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-05-2014; American Society of Hematology
• Subjects: Ataxia Telangiectasia Mutated Proteins - genetics; B-Lymphocytes - metabolism; Burkitt Lymphoma - genetics; Burkitt Lymphoma - pathology; Chromatin - genetics; Chromatin - metabolism; Cyclin D1 - genetics; DNA Helicases - genetics; DNA-Binding Proteins - genetics; Epigenesis, Genetic; Exome - genetics; Gene Regulatory Networks; Genomics; Germinal Center - metabolism; Germinal Center - pathology; Histone-Lysine N-Methyltransferase - genetics; Histones - genetics; Histones - metabolism; Humans; Lymphoid Neoplasia; Lymphoma, Mantle-Cell - genetics; Lymphoma, Mantle-Cell - pathology; Methylation; Mutation; Neoplasm Proteins - genetics; Nuclear Proteins - genetics; Repressor Proteins - genetics; Retinoblastoma Protein - genetics; Sequence Analysis, DNA; Telomere-Binding Proteins - genetics; Transcription Factors - genetics; Tumor Suppressor Protein p53 - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-07-517177

In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.
•We identified novel recurrently mutated genes, including WHSC1, RB1, POT1, and SMARCA4, through exome sequencing of 56 cases of MCL.•Genetic mutations defining MCL and Burkitt lymphoma were associated with the epigenetically defined chromatin state of their respective B cells of origin.